Principal Investigator/Program Director (Last, First, Middle); Michel, Thomas PROJECT 2: "KLF2, Diabetes, and Endothelial Gene Expression." Mukesh K. Jain, Project Leader Abstract: The vascular endothelium is a critical integrator and transducer of various physiologic and pathologic stimuli. In diabetes, the enhanced production of pro-inflammatory cytokines, advanced glycation endproducts, and activation of specific signaling pathways (e.g. protein kinase C, PKC) alter endothelial function. Characteristic abnormalities include reduced endothelium dependent vasodilation, enhanced expression of leukocyte adhesion molecules, and increased elaboration of procoagulant factors. As a consequence of these effects, diabetic patients exhibit an accelerated and aggressive form of micro- and macro-vascular arteriopathy. KLF2 is a member of the Kruppel-like family of zinc-finger transcription factors that is expressed in vascular endothelial cells and induced by laminar flow. KLF2 overexpression in endothelial cells potently induces endothelial nitric oxide synthase (eNOS) expression and activity. In addition, KLF2 inhibits the inflammatory cytokine and PKC mediated induction of adhesion molecules (e.g. VCAM-1, E-selectin) and procoagulant factors (e.g. PAI-1, tissue factor). Conversely, KLF2 expression in endothelial cells is strongly inhibited by hyperglycemia, advanced glycation products, activation of PKC pathway, and pro-inflammatory cytokines. On the basis of these observations we hypothesize that (1) KLF2 is a key regulator of endothelial cell function under physiologic states and (2) reduction in KLF2 expression by pathologic stimuli is a critical event in the development of diabetic vascular disease. The studies below will examine the molecular mechanisms regulating KLF2 expression in endothelial cells and the functional consequences of altering KLF2 levels on endothelial function in vitro and in vivo. These studies will provide insight into the role of this factor in endothelial cell biology and may serve as the foundation for novel strategies to modulate endothelial cell function under physiologic and pathologic states.